Connective tissue is the framework upon which other tissue, i.e., epithelial, muscle, and nervous tissues, are supported. Connective tissue generally includes individual cells not directly attached to one another and held within the extracellular matrix. The extracellular matrix, in turn, includes the ground substance (e.g., the minerals of bone, the plasma of blood, etc.) and a fibrous component including collagen fibers and elastin fibers.
Connective tissue can assume widely divergent architectures, ranging from blood, in which the fibrous component is absent and the ground substance is fluid, to dense connective tissue, which includes a relatively high proportion of extracellular fibers and may contain little of the other connective tissue components. There are many specialized types of connective tissue, one example being elastic tissue, in which elastic fibers are the major component of the tissue and the amount of factors commonly found in other types of connective tissue, such as collagen and proteoglycans, may be minimal.
Elastin is quite abundant in connective tissue and is the protein constituent of the elastic fibers found in most connective tissue. For instance, elastin is the most abundant extracellular matrix protein found in the aortic wall and is prevalent in skin and lung tissues. Elastic fibers of connective tissue are responsible for the elasticity and recoil of the tissue. Elastic fibers are formed from the microfibril peripheral scaffold and amorphous core cross-linked elastin. More specifically, amorphous elastin is formed from monomers of soluble tropoelastin that are cross-linked together to form insoluble amorphous elastin. The microfibril scaffold includes numerous proteins (e.g., glycoproteins, fibrillin, elastin receptor, etc.) and organizes and surrounds the core of amorphous elastin of the fibers. Unlike collagen, elastic fibers can uncoil into a more extended conformation when the fiber is stretched and can recoil spontaneously as soon as the stretching force is relaxed.
Elastin degradation is a common feature in much pathology including aneurysm (e.g., abdominal aortic aneurysm, brain aneurysm), chronic obstructive pulmonary disease (COPD), chronic kidney disease, hypertension, α-1 antitrypsin deficiency, Marfan's syndrome, and others, and can also occur naturally over time leading to loss of smoothness and firmness in skin as we age. Elastic fiber degradation is often caused by enzymes including elastase enzymes and matrix metalloproteinase (MMP) enzymes that can attack either or both of the elastin and the scaffolding proteins of the fiber. Such enzymes can be secreted by native cells such as vascular cells in arteries, dermal and lung fibroblasts in skin and lung, respectively, as well as by infiltrating inflammatory cells.
While many aspects of the methods and biological interactions leading to elastic fiber degradation remain unknown, many compounds have been developed or discovered that can help prevent or treat damage to tissue due to elastin degradation, such as certain polyphenolic compounds, statins, anti-inflammatory drugs, enzyme inhibitors, and the like. Unfortunately, typical delivery of such compounds is either systemic or localized delivery in which much of the compound is expected to fail to reach the target. Such delivery methods lead to the utilization of large doses of the compounds, which, in addition to adding to costs, can also cause toxic side effects to the patient. In addition, non-targeted delivery mechanisms can allow the compounds to interact with other, non-targeted structures in the body, which can alter normal function and lead to unwanted side effects.
What are needed in the art are methods and compounds that can specifically target treatment compounds to damaged elastic fibers for prevention or treatment of damage due to elastin degradation.